1. Field of the Invention
The present invention relates to the disease gene of rheumatoid arthritis present in the human X chromosome and a method for diagnosing rheumatoid arthritis by detecting the presence of the disease gene or its expression product.
2. Description of Related Art
Although aspects, particularly the pathological process, of arthritis and arthritis mutilans which cause rheumatoid arthritis, have been clarified through various investigations, because most autoimmune diseases associated with rheumatoid arthritis developed or worsen into the disease only when various causative factors coincide, the interaction itself of multiple factors must be clarified to understand the disease and to develop appropriate methods of treatment.
The number of patients with rheumatoid arthritis in the world is 1% or less (N. Engl. J. Med. 322: 1277-1289, 1990), but among sibilings of patients, over 8% develop the disease (Cell. 85: 311-318, 1996), which leads to the notion that some genetic factor may be involved. However, molecular genetic procedures and genetic engineering processes used conventionally to discover the genetic factor of diseases may not be effective for autoimmune diseases. Such problem is caused by the fact that autoimmune diseases do not develop through mechanisms as simple as those of cancer, wherein abnormal growth of one mutated gene occurs. Further, although classical genetic procedures which search for genetic basis of a disease revealed that autoimmune diseases are caused by multiple genetic factors, it has not been successful in discovering its entrails or its body. Thus, almost nothing about the entity, or even the locus, of genes associated with rheumatoid arthritis has been known.
By performing linkage analysis using microsatellite markers on rheumatoid arthritis patients and their relatives, the present inventors identified three loci of rheumatoid arthritis genes (International Immunology 10(12): 1891-1895, 1998; Journal of Clinical Rheumatology 4(3): 156-158, 1998) and filed a patent application for the following disease genes (PCT/JP98/01665).
(1) A disease gene of rheumatoid arthritis located within xc2x11 centi Morgan vicinity of a DNA sequence on human chromosome 1 to which microsatellite marker(s) D1S214 and/or D1S253 hybridize(s)
(2) A disease gene of rheumatoid arthritis located within xc2x11 centi Morgan vicinity of a DNA sequence on human chromosome 8 to which microsatellite marker D8S556 hybridizes.
(3) A disease gene of rheumatoid arthritis located within xc2x11 centi Morgan vicinity of a DNA sequence on human chromosome X to which microsatellite marker(s) DXS1001, DXS1047, DXS1205, DXS1227 and/or DXS1232 hybridize(s).
The present inventors identified, as a result of further studies on each of the rheumatoid arthritis genes specified in the above-described previous application, the specific gene regarding the disease gene (3) described above and determined its molecular structure.
In order to solve the above-described problems, the present invention provides a cDNA of a disease gene for rheumatoid arthritis, which has the base sequence of SEQ ID NO: 1.
The present invention also provides a DNA fragment, which is a part of such cDNA and necessarily contains the base sequence from 2693rd to 2702nd of SEQ ID NO: 1, a protein expressed by the above disease gene, a peptide which is a part of such protein, and an antibody against such protein.
Further, the present invention provides a method for diagnosing rheumatoid arthritis comprising the detection of the mRNA from the above disease gene or the above protein in a biological specimen.
The present invention further provides a method for the functionally complementing Dbl deficiency.